Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Department of Thoracic Surgery, the First Affiliated Hospital of Guangzhou Medical University, the State Key Laboratory of Respiratory Disease, and the National Clinical Research Centre for Respiratory Disease, Guangzhou 510120, China.
Cancer Cell. 2023 Sep 11;41(9):1621-1636.e8. doi: 10.1016/j.ccell.2023.07.012. Epub 2023 Aug 17.
Brain metastasis of lung cancer causes high mortality, but the exact mechanisms underlying the metastasis remain unclear. Here we report that vascular pericytes derived from CD44 lung cancer stem cells (CSCs) in lung adenocarcinoma (ADC) potently cause brain metastases through the G-protein-coupled receptor 124 (GPR124)-enhanced trans-endothelial migration (TEM). CD44 CSCs in perivascular niches generate the majority of vascular pericytes in lung ADC. CSC-derived pericyte-like cells (Cd-pericytes) exhibit remarkable TEM capacity to effectively intravasate into the vessel lumina, survive in the circulation, extravasate into the brain parenchyma, and then de-differentiate into tumorigenic CSCs to form metastases. Cd-pericytes uniquely express GPR124 that activates Wnt7-β-catenin signaling to enhance TEM capacity of Cd-pericytes for intravasation and extravasation, two critical steps during tumor metastasis. Furthermore, selective disruption of Cd-pericytes, GPR124, or the Wnt7-β-catenin signaling markedly reduces brain and liver metastases of lung ADC. Our findings uncover an unappreciated cellular and molecular paradigm driving tumor metastasis.
肺癌脑转移导致高死亡率，但转移的确切机制仍不清楚。在这里，我们报告肺腺癌（ADC）中源自 CD44 肺癌干细胞（CSC）的血管周细胞通过 G 蛋白偶联受体 124（GPR124）增强的跨内皮迁移（TEM）强烈导致脑转移。血管周围龛位中的 CD44 CSC 产生肺 ADC 中大多数血管周细胞。CSC 衍生的周细胞样细胞（Cd-pericytes）表现出显著的 TEM 能力，可有效侵入血管腔，在循环中存活，渗出到脑组织中，然后去分化为致瘤性 CSC 形成转移。Cd-pericytes 特异性表达 GPR124，激活 Wnt7-β-catenin 信号通路，增强 Cd-pericytes 的 TEM 能力，促进浸润和渗出，这是肿瘤转移过程中的两个关键步骤。此外，选择性破坏 Cd-pericytes、GPR124 或 Wnt7-β-catenin 信号通路可显著减少肺 ADC 的脑和肝转移。我们的研究结果揭示了一个未被重视的细胞和分子范式，驱动肿瘤转移。
